While the progress in identifying major cancer susceptibility genes has been gratifying, our ability to intervene at the molecular level in order to reduce the risk associated with mutations in these genes is embryonic. We are in urgent need of safe and effective strategies through which the risk of cancer in mutation carriers can be reduced now. A strategic planning process within DCEG led to a recommendation that the Division expand its activities in the area of intervention studies, a proposal which has been endorsed by the Intramural Division Directors. (a) Concurrent with this process, we have initiated efforts to support the breast cancer and colon cancer chemoprevention trials currently underway within NCI's Center for Cancer Research by urging members of our cancer-prone families to participate in these important studies, and coordinating referrals for those who are interested. Trials currently accruing patients include a Phase II breast cancer prevention trial [open to women at increased risk of breast cancer] utilizing the selective estrogen receptor modulator raloxifene, and a Phase II colon cancer trial [targeting members of hereditary nonpolyposis colorectal cancer syndrome families] employing the selective COX-2 inhibitor, celecoxib. (b) Also under discussion is the possibility of initiating a series of Phase II clinical trials (in collaboration with the University of Arizona Cancer Center) among patients with dysplastic nevi, a known melanoma precursor, to seek biologically active compounds which might hold promise as topical skin cancer chemoprevention agents. These studies have evolved from the Arizona Cancer Center's Skin Cancer Chemoprevention Program Project Grant. Candidate agents which would be studied include topical tretinoin (all-trans retinoic acid), 9-cis retinoic acid, diflouromethylornithine (DFMO), epigallotcatechin gallate, perillyl alcohol and sodium salicylate. A panel of surrogate endpoint biomarkers would be employed as indicators of biological activity. This project would represent a natural evolution of DCEG's long-standing interests in hereditary melanoma and melanoma precursors. (c) A study of the prevalence of BRCA1/2 founder mutations is among 1000 Ashkenazi Israelis with prostate cancer has provided additional support for the hypothesis that prostate cancer is part of the disease spectrum for men with BRCA mutations. Discussions have now begun with collaborators from the Urological Oncology Branch/Center for Cancer Research regarding the possibility of designing a prostate cancer intervention trial that would target the men from CGB's cohort of mutation-positive hereditary breast/ovarian cancer families. (d) Our study of persons from families with one of a variety of inherited bone marrow failure syndromes (e.g., Fanconi's anemia) will open to patient accrual in early 2002. Among the non-hematologic malignancies which occur excessively in these individuals are squamous cell carcinomas of the oral cavity and esophagus. Participants in this study will undergo intensive evaluation in search of both clinical and molecular abnormalities which might represent cancer precurosrs. The role of the human papilloma virus (HPV) in the etiology of these cancers will be explored. If suitable clinical or molecular endpoints can be identified, consideration will be given to the development of an intervention program which would target persons from these high-risk families. (e) An issue yet to be resolved is the role that CGB might play in the planning, conduct and analysis of national, multi-institutional Phase III intervention trials which target genetically high-risk populations, perhaps in collaboration with such organizations as the Cancer Genetics Network, the Cooperative Family Registries for Breast, Colon Cancer, the Early Detection Resource Network, site-specific SPORES, etc. This issue is most likely to require formal consideration with regard to the possibility of mounting a Phase III randomized chemoprevention trial for women who are carriers of mutations in the BRCA1/2 genes. At present, there is no single organization in the United States with all of the capabilities required to undertake such a study. The clinical trials cooperative groups have expertise, resources and infrastructure relative to the conduct of large randomized studies, but historically have not had access to genetically high-risk populations. Similarly, CGN and CFR have access to the right kind of study subjects, but no experience in the conduct of clinical trials. The Clinical Genetics Branch may be optimally positioned to play a central role in such studies.